Tumor necrosis factor inhibitors and janus kinase inhibitors in the treatment of cicatricial alopecia: A systematic review

Background Cicatricial alopecia (CA) refers to various conditions that result in permanent hair loss. Treatment of CA has always been challenging. Regarding immune-mediated pathophysiology for many CA subtypes, the administration of Janus kinase (JAK) and tumor necrosis factor (TNF) inhibitors have potentiated the treatments of CA. Methods After a thorough systematic search in PubMed/Medline, Embase, Web of Science, Scopus, Google Scholar, ClinicalTrials.gov, and WHO ICTRP, a total of 3,532 relevant records were retrieved and screened. Accordingly, 56 studies met the eligibility criteria and entered the review. Results Among JAK inhibitors, oral tofacitinib was the most frequently reported and the most effective treatment in improving signs and symptoms of CA with minimal adverse effects (AEs). Baricitinib was another JAK inhibitor with sustained improvement while causing mild AEs. As a TNF inhibitor, adalimumab induced a rapid and stable improvement in signs and symptoms in most patients with rare, tolerable AEs. Thalidomide was the other frequently reported yet controversial TNF inhibitor, which caused a rapid and significant improvement in the condition. However, it may result in mild to severe AEs, particularly neuropathies. Infliximab is a TNF inhibitor with mostly favorable results, albeit in a few patients caused treatable dermatological AEs. Apremilast and certolizumab pegol caused an incomplete amelioration of signs and symptoms with no AEs. Lenalidomide is another TNF inhibitor that can induce temporary improvement in CA with probable AEs. It is noteworthy that utilizing adalimumab, infliximab, etanercept, golimumab, and an anonymous TNF inhibitor has induced paradoxical CA and other A.E.s in some patients. Conclusion Recent studies have recommended JAK and TNF inhibitors, especially oral tofacitinib and adalimumab, as a new modality or adjuvant therapy to previous medications for primary CA. Nonetheless, monitoring AEs on a regular basis is suggested, and further extensive studies are required before definitive recommendations.


Introduction
Cicatricial alopecia (CA) is a heterogeneous group of cutaneous disorders characterized by fibrosis or hyalinized collagen replacing follicles, leading to irreversible destruction of hair follicles with subsequent scarring and baldness [1,2].The two types of CA are classified according to the target inflammation structure and the mechanisms responsible for the destruction of follicles, including primary and secondary forms [3].Primary CA is caused by direct inflammatory damage to the hair follicle epithelium, which targets the hair follicle itself.Secondary CA results from inflammation or mechanical damage to surrounding tissues, affecting and destroying hair follicles.Physical damage, burns, radiation, infections, tumors, and chronic inflammatory diseases such as linear morphea can progress both types of alopecia.Based on the predominant cell type in the inflammatory infiltrate, primary CA is also categorized into five subtypes:: (I) Lymphocytic, including lichen planopilaris (LPP), frontal fibrosing alopecia (FFA), pseudopelade of brocq (PPB), and central centrifugal cicatricial alopecia (CCCA); (II) Neutrophilic, including folliculitis decalvans (FD) and dissecting cellulitis of the scalp (DCS), also known as perifolliculitis capitis abscedens et suffodiens (PCAS); (III) Mixed, including erosive pustular dermatosis of the scalp (EPDS) and folliculitis (acne) keloidalis; (IV) Nonspecific, defined as idiopathic CA with indefinite clinical and histopathological findings [1].CA treatment aims to halt or slow the destruction of follicles, minimize the symptoms, and increase the chance of hair regrowth [3].
The tumor necrosis factor-alpha (TNFα) is the first cytokine that appears in the blood, secreted primarily by activated macrophages and other immune cells, facilitating the initiation and regulation of inflammation in the body [4,5].TNFα, as a mediator of autoimmune disease, significantly contributes to the pathogenesis of several chronic inflammatory and rheumatic diseases [6,7].TNF inhibitors, a class of drugs used to treat various inflammatory diseases, were investigated initially for treating rheumatoid arthritis [8].The U.S. Food and Drug Administration (FDA) approved four types of TNF inhibitors for treating dermatological conditions, including plaque psoriasis [9].
The Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathways play an integral role in intracellular cytokine signaling [10].The Janus kinase (JAK) family comprises four members: JAK1, JAK2, JAK3, and Tyrosine kinase 2 (TYK2) [11].JAK-STAT signaling pathways are of great significance in regulating the growth, development, and differentiation of immune and hematopoietic cells [12].JAK inhibitors are a class of medications that work by inhibiting the phosphorylation and activation of different JAKs, thus blocking the cascades of cytokines-related inflammation [13,14].
Despite improvements in the diagnosis and treatment of CA, the explanations for the exact pathogenesis of CA are still largely uncertain [15].Prior investigations suggest multiple therapeutic options for CA, such as topical or systemic corticosteroids, antibiotics, mycophenolate mofetil, minoxidil, and systemic retinoids [1,3,16].However, utilizing previous treatment approaches was not compelling enough to treat CA patients and may induce following drug-related complications and high incidence of adverse events (AEs) and relapses [3].Based on intracellular inflammatory mechanisms associated with CA, new medications with specific anti-inflammatory pathways could be promising in managing CA with fewer AEs [17].Recently, TNF and JAK inhibitors, previously proven to treat many dermatological and autoimmune diseases, were applied to CA patients to evaluate the promise and perils of these classes of drugs [9,10,14,18].In this study, we aim to systematically assess all aspects of TNF and JAK inhibitors in the management of CA.

Material and methods
The current systematic review was conducted according to the PRISMA checklists which are attached as supplementary documents (S1 and S2 Tables).

Search strategy
A thorough systematic search was conducted in databases, including PubMed/Medline, Embase, Web of Science, and Scopus, as well as the Google Scholar search engine, Clinical-Trials.gov,and WHO ICTRP.A complete list of search terms is available in supplementary documents (S3 Table ).

Eligibility criteria
Studies were eligible for inclusion in this systematic review if they were clinical trials, case reports, case series, or observational studies with an available English full text.The eligible source populations were individuals of any age treated with JAK inhibitors or TNF inhibitors for any type of CA.Reviews, experimental studies (in vitro/ex vivo or animal studies), and studies exclusively about non-cicatricial alopecia were excluded.

Data extraction and study selection
Two independent reviewers (NH, AH) conducted separate data extraction processes for all the eligible studies as follows: (I) study characteristics (author, year, design, sample size, treatment, outcome measurement, and follow-up duration), (II) patients' characteristics (age, gender, cause of CA, baseline condition, disease duration, previous treatments), and (III) results (efficacy, outcome, recurrence, and A.E.s).Ultimately, the corresponding authors meticulously reviewed any disparities and disagreements in the extracted data and provided guidance for creating the final tables containing the extracted data.

Risk of bias assessment
Two investigators evaluated the methodological quality of the selected studies and the risk of bias independently (NH, AH).For these assessments, the National Institute of Health (NIH) Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies [19], the NIH Tool for Before-After (Pre-Post) Studies with No Control Group [20], and Murad MH et al. for case series and case reports [21] were utilized, respectively (S4 to S6 Tables).In summary, the bias assessment of the included studies in this systematic review revealed varying levels of methodological quality.The evaluation of before-after studies with no control group (S4 Table ) showed a range of quality scores from 4 (Poor) to 8 (Fair), highlighting issues such as unclear participant selection and inadequate sample sizes.Observational cohort and cross-sectional studies (S5 Table) received a single high-quality score of 9 (Fair), indicating robust methodology.In contrast, case reports and case series (S6 Table) had total quality scores varying from 2 to 6, with common issues including lack of patient representation, unclear exposure and outcome ascertainment, and incomplete reporting.

Search results
A total of 3,532 records were found in a search up to December 24 th , 2022.The number of 508 duplicates were detected and removed by the software.In the first and second phases of the screening, 917 studies were reviewed by reading the titles and abstracts to select the relevant publications by two independent reviewers (NH, AH).Disagreements were resolved with discussion or the consensus of the corresponding authors.Full texts were reviewed in the last screening phase, and 56 publications were included for data extraction.The inclusion process of our study-based PRISMA flowchart is illustrated in Fig 1.

Characteristics of eligible studies
The included studies encompass forty-five case reports, seven case series, three interventional studies, and one retrospective cohort.Among these, nine studies focused on JAK inhibitor therapies, while thirty-four studies investigated TNF inhibitor therapies for the treatment of CA.Moreover, fourteen studies reported CA as an AE of the treatment with TNF inhibitors.The sample size of the selected studies ranged from one to 118 patients, and a total of 342 patients were presented in the included articles.However, some of these patients were not compatible with the topic of the study and were not included in the results.

Janus kinase inhibitors
Nine studies reported various JAK inhibitors as treatments for CA in a total of 49 subjects.The results of these studies are completely demonstrated in Table 1.

Lichen planopilaris (LPP) and frontal fibrosing alopecia (FFA).
Six studies investigated a total of 49 peers with LPP or FFA treated with JAK inhibitors.Oral tofacitinib therapy was the most frequent treatment and resulted in a mostly sustained and significant improvement in lichen planopilaris activity index (LPPAI) [22,23], signs, and symptoms [22,[24][25][26].A challenge/rechallenge phenomenon was reported in some studies, indicating the dependence of clinical improvement on the continuation of the medication [22,23,26].Furthermore, cessation of hair loss [26] and even hair regrowth [22,25] was observed in a number of patients.Concurrently, it's important to highlight that while topical tofacitinib showed effectiveness in a majority of cases, it fell short in terms of both effectiveness and sustainability when compared to its oral counterpart.[24].
Baricitinib was administered to treat 12 patients who failed previous treatments, including tofacitinib [27].Most patients experienced an initial improvement in LPPAI; however, less than half maintained favorable results after six months.AEs were said to be rare, minimal, and tolerable in all subjects.
Notably, one has resisted the previous therapy with certolizumab pegol [29].Both patients expounded an almost complete amelioration in signs and symptoms with no AEs during their follow-up period.

Folliculitis decalvans (FD).
Three patients with relatively long-term FD showed a rapid and significant improvement while on tofacitinib therapy [30].Minimal AEs were reported in two cases.Nevertheless, recurrence was spotted in all three after discontinuing the therapy.

Tumor necrosis factor inhibitors
In 34 publications assessing the effect of TNF inhibitors in managing CA, multiple TNF inhibitors were utilized in 141 patients.The individual results of the studies are consolidated in Table 2.

Lichen planopilaris (LPP).
Treatment of LPP using adalimumab resulted in a remarkable improvement in signs and symptoms as well as hair regrowth in two patients [31,32]; One was refractory to a previous TNF inhibitor (certolizumab pegol) and was simultaneously affected by hidradenitis suppurativa (HS) and RA [31].The other patient experienced a recurrence of the disease three months after the discontinuation of adalimumab [32].
Thalidomide therapy for LPP led to controversial results in two studies.A group of patients experienced continuous or even deteriorating hair loss as well as a case of thalidomide-related slowly progressive sensory neuropathy [33].In contrast, another study demonstrated thalidomide therapy resulted in rapid hair regrowth and stable outcomes in a subject with LPP [34].

Folliculitis decalvans (FD).
Twenty-eight patients were treated with adalimumab for FD.This treatment resulted in a relatively rapid and mainly sustained improvement in the condition of most patients despite uncommon and tolerable AEs [32,[35][36][37].However, a young patient did not respond to the treatment after three months [38].It is also claimed that one patient with a satisfactory response to adalimumab had previously received apremilast, another TNF inhibitor, with no improvement [36].The phenomenon of challenge and rechallenge [35] and flare-ups following medication discontinuation [36] were observed in a few of the cases.Despite a quick response and near-complete improvement in some signs and symptoms (with positive challenge/ rechallenge phenomenon) in one patient, apremilast did not lead to hair regrowth [39].
Other TNF inhibitors, such as infliximab, showed a rapid improvement in inflammatory lesions without AEs or recurrence in one FD patient [40].In spite of the latter favorable result of infliximab in treating FD, a study reported the prompt occurrence of severe eruptive condyloma acuminata in the perineal region of one patient [41].However, the lesions were rapidly resolved with proper treatments.Additionally, certolizumab pegol led to a noteworthy improvement in a patient with FD, although the improvement was not complete [42].
In the patient with secondary failure of adalimumab therapy, switching to infliximab stabled the disease after 16 weeks [53].Two other patients receiving infliximab therapy for DCS (PCAS) had a similar clinical response.According to the details, one of the DCS (PCAS) cases , MTX (6) , Clobetasol, Clindamycin, Rifampin, Leflunomide, Sulfasalazine Adalimumab 160 mg (7) , 80 mg, 40 mg SC (8) q (9) 1w (10) (each for once)   experienced an abrupt, notable amelioration in signs and symptoms after the first therapy session, followed by a delayed halting in the scarring process.Nonetheless, the patient experienced an AE in the form of reversible psoriasiform exanthema [57].Infliximab in other patients maintained a satisfactory clinical response as well as hair regrowth with no AE [45].
Furthermore, two patients with a history of unsuccessful thalidomide therapy were switched to lenalidomide.Both patients were also affected by systemic lupus erythematosus (SLE).One of them experienced a rapid clinical response and improvement in signs and symptoms, while the other one failed to reach any clinical improvement.Moreover, disturbances in laboratory test results in both patients and vasculitis, in addition to cellulitis of the legs in the non-responding patient, were reported as AEs [64].

Subacute cutaneous lupus erythematosus (SCLE) and pseudopelade of brocq (PPB).
In a patient with SCLE and concomitant SLE, thalidomide therapy resulted in a complete clinical response with no severe AEs and amelioration in signs and symptoms as well as cessation of hair loss, and no hair regrowth was observed [54].Failure in clinical improvement was also documented in two patients with PPB.

Tumour Necrosis Factor (TNF) inhibitor therapy-induced cicatricial alopecia
Thirteen studies reported the induction of CA following the prescription of TNF inhibitors for different clinical conditions in a total of 14 individuals.The results of these studies are presented in Table 3.
3.5.1.Adalimumab.Adalimumab therapy in some patients resulted in several AEs, including widespread DLE, inflammatory joint pain, abnormal laboratory tests [65], severe scalp psoriasis, moderate gastrointestinal (GI) symptoms [66], LPP, rapidly progressive skin lesions [67], and scarring alopecia [65][66][67].Discontinuation of the treatment caused an improvement in skin manifestations of most patients [65,67], while stopping the medication was not enough in one patient who was eventually commenced on belimumab therapy, leading to a delayed and partial improvement in adalimumab-induced skin lesions [65].
In another study, a patient with Crohn's disease (CD) experienced adequate control of the condition after receiving infliximab [68].Due to the incidence of palmoplantar pustulosis and erythematous scaly plaques on the scalp, infliximab was substituted with adalimumab, and subsequently, the palmoplantar lesions disappeared.However, several AEs, including worsening of the scalp, CA in the form of FD, and psoriasiform dermatitis with parakeratosis, occurred as well.Finally, after suspension of adalimumab and initiation of different therapies, treatment with ustekinumab was able to completely resolve the scalp disease with minimal residual scars.
Lastly, etanercept was administered for the treatment of extended oligoarthritis, bilateral optic nerve drusen, and an asymptomatic arachnoid cyst in a patient who showed good results [69].The patient was then switched to adalimumab as maintenance therapy.Three months following the initiation of adalimumab treatment, the patient exhibited a recurrence of LPP, arthritis, and the appearance of discoid plaques on the hips and thighs.Various medications were administered, and complete hair regrowth was finally achieved by tocilizumab therapy.
) N.R. (10) Clinical condition Improvement of psoriasis 9x8 cm (11) LPP (12) alopecic patch Terbinafine 125 mg PO (13) QD (14) (for 4 w) Class I TCS (15) Topical Tacrolimus No clinical improvement 24 Amschler, 2018 [68] C.R. 3.5.2.Infliximab.In two out of three patients receiving infliximab therapy, the occurrence of LPP and other AEs was reported [70,71].Deflazacort was added to the treatment regimen of one of the patients and caused a mild improvement in LPP without any new lesions [70].Nevertheless, the other patient experienced a challenge/rechallenge phenomenon regarding both the efficacy and AEs of infliximab therapy.After trying different medications, cessation of infliximab following prolonged prednisone and betamethasone valerate treatments resulted in a partial improvement of the AEs [71].
The third patient was receiving infliximab for CD and experienced scalp psoriasis and CA in the form of FD [72].After switching from infliximab to other treatments, a remarkable improvement in the scalp condition, complete hair regrowth, and stabilization of CD were obtained.
3.5.3.Etanercept.Etanercept improved different manifestations of psoriasis in two patients while causing CA in the form of LPP [73,74].The phenomenon of challenge and rechallenge regarding both the therapeutic effect on psoriasis and the recurrence of alopecia was reported [74].
Moreover, the AEs of etanercept therapy were comparably more severe in a patient with RA [75] and DLE.Although the treatment temporarily stabilized the baseline conditions, it ultimately led to the development of CA and SLE, which were only responsive to the discontinuation of etanercept.
3.5.4.Golimumab and others.Golimumab therapy in a patient with concomitant atopic dermatitis (AD), ankylosing spondylitis (AS), and localized alopecia areata (AA) was associated with an AA exacerbation, CA, and photodistributed lupus-like cutaneous reaction [76].Adding sun protection, topical clobetasol solution, and intralesional triamcinolone acetonide (TAC) injections were beneficial for improving the alopecic lesions and stabilization of AS.
Lastly, an anonymous TNF inhibitor was used to treat inflammatory bowel disease (IBD) in a patient, resulting in psoriatic CA of the scalp and asymptomatic plaques on the body [77].In order to manage the condition, discontinuation of the TNF inhibitor, as well as the application of super-potent topical steroids, was necessary.

Discussion
We systematically reviewed 56 studies regarding the efficacy and safety of JAK and TNF inhibitors in treating CA.A total of 342 patients with different causes of alopecia, including LPP, FFA, EPDS, FD., DCS (PCAS), DLE, PPB, SCLE, TNF inhibitor therapy-induced CA, and some non-cicatricial subtypes (were excluded from the current review) were reported in the studies.Among the included studies, nine and 34 articles assessed the therapeutic effects of JAK and TNF inhibitors in CA, respectively.The results of the current systematic review support that JAK and TNF inhibitors are potential therapeutic options for managing CA.
One proposed pathophysiology for CA argues the attack of the hair follicles by one's immune system, resulting in inflammation and damage to the stem cells in the follicles and subsequent scarring and permanent hair loss [1,2].JAK inhibitors can suppress the activity of several cytokines and growth factors, such as interferon-gamma, interleukin (IL)-2, IL-6, and TNF, which may be involved in the pathogenesis of CA [13,14].As a result of inhibiting these cytokines, JAK inhibitors can prevent further damage to the hair follicles by reducing inflammation.Additionally, the inhibition of the JAK-STAT pathway may promote hair regrowth by activating and proliferating the stem cells embedded in the hair follicles, though the actual mechanism is unknown [78].
Tofacitinib (oral or topical) and baricitinib are both effective in improving CA; however, the effectiveness, sustainability of outcomes, and frequency of usage were relatively higher with oral tofacitinib.Hair regrowth was reported, and AEs were rare, mild, and tolerable in all patients.Tofacitinib targets the activity of JAK1 and JAK3, while baricitinib inhibits JAK1 and JAK2.These receptors render the signaling pathways of multiple cytokines and growth factors, contributing to inflammation in the follicles and immune-mediated damage [79].
In addition, JAK inhibitors have been effective in the induction of hair regrowth and improved the quality of life in patients with AA [80].It seems that oral treatment has a remarkably higher response rate than the topical form of the medication.The response rate was no different between pediatric and adult patients.Consistent with these results, another study concluded that oral administration was highly favorable [81].The topical formulations did not provide a satisfactory response for the patients.Notably, these agents are required to be administered chronically to maintain long-term response [82].
TNF is a proinflammatory cytokine that plays a crucial role in the pathogenesis of some autoimmune and inflammatory disorders [6,82].Upregulation of TNF in CA leads to the immune-mediated destruction of the hair follicles.TNF inhibitors, such as adalimumab, etanercept, and infliximab, can bind to and neutralize TNF, reduce inflammation, and prevent hair follicles from further damage [8,9].
Adalimumab is an effective treatment for LPP, FD, and DCS (PCAS); most patients showed a rapid response and sustained clinical improvement, while hair regrowth was observed only in some.On the other hand, thalidomide therapy for LPP and DLE was of variable outcomes; some patients experienced continued or deteriorated hair loss, and others showed rapid hair regrowth and maintained results.Despite substantial improvement in signs and symptoms, thalidomide therapy may cause mild to severe AEs.
Infliximab therapy is an effective alternative to adalimumab for CA.Some patients experienced excellent clinical improvement and hair regrowth.Nonetheless, some reversible AEs, such as psoriasiform exanthema or severe eruptive condyloma acuminata in the perineal region, were observed.Certolizumab pegol therapy resulted in a remarkable amelioration of signs and symptoms of FD, though a complete improvement has not been achieved.The results suggested that TNF inhibitors, particularly adalimumab, can effectively treat CA.However, there is limited evidence to determine the efficacy and safety of such medications to treat each subtype of CA.
Recent literature expounded that people with a background of rheumatological or gastrointestinal disorders may experience induced new-onset psoriasis while receiving TNF inhibitors.Reversible alopecia was a random AE of treatment with TNF inhibitors [83,84].Compared to these studies, our systematic review focused on using TNF and JAK inhibitors in treating CA, a more severe, scarring, and difficult-to-treat type of alopecia.Based on existing evidence, both TNF and JAK inhibitors can effectively alleviate signs and symptoms of CA with minimal AEs.Nonetheless, the evidence of JAK inhibitors in treating CA was limited.
The literature suggests that TNF inhibitors can cause AEs, including cancer, serious infections, heart failure, and demyelinating disorders, such as multiple sclerosis and lupus-like syndrome, after administration in predisposed individuals [85].Therefore, patients receiving these medications should be closely monitored and regularly followed up.Moreover, the potential of thalidomide in treating cutaneous conditions has recently re-emerged precisely regarding its benefits in treating specific dermatological disorders unresponsive to traditional therapies [86].However, due to its teratogenic effects, thalidomide should also be regulated.Hence, it can only be prescribed under strict conditions and obligatory contraception for women of childbearing age [87].
Recent investigations are constrained by several factors derived from smaller studies such as case reports and case series.Besides, observer bias is a common issue in current evidence, which occurs when studies are not blinded during treatment and outcome assessment.
Selection and publication biases are also significant since only positive results will likely be published.A small sample size of the patients also limits statistical power.Despite all these issues, our results add to the growing literature on immunomodulatory therapies to treat CA.JAK inhibitors, especially oral tofacitinib, are promising options for treating LPP and FFA with minimal AEs.Although TNF inhibitors can effectively treat LPP and FD, more studies are mandatory to investigate their long-term efficacy and safety in different age groups.

Conclusion
In summary, the results of this systematic review convey valuable insights for clinicians in choosing appropriate medications for treating CA based on patient conditions.It is imperative to note that JAK and TNF inhibitors, particularly oral tofacitinib and injectable adalimumab, can be considered as new replacements or adjuvants to previous therapies for CA, particularly primary subtypes.Although these medications are efficacious, maintained, safe, and feasible treatments in most cases, patients should be regularly monitored for AEs.Other JAK and TNF inhibitors also demonstrated therapeutic potential for treating CA, but their controversial clinical effects and inconsistent AEs require close monitoring.Furthermore, some classes of JAK and TNF inhibitors have not been investigated in the management of CA to date.Lastly, more explanation is mandatory regarding the rare alopecia-inducing AE of TNF inhibitors in some conditions; it is crucial to halt TNF inhibitor therapy whenever such AEs appear before causing scar and irreversible baldness.Albeit confirmation of these findings requires large-scale randomized trial studies in the future prior to definitive recommendation.

Table 2 .
Characteristics of eligible studies utilizing tumor necrosis factor-alpha inhibitors for the cicatricial alopecia treatment.
Photo documentationClinical condition Patient-reported outcomes Progressive decrease in pain and swelling after 1 m Complete resolution of inflammatory lesions after 7 m